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Article

Triorganoindium Reagents in Rh-Catalyzed C–H Activation/C–C Cross-Coupling Reactions of 2-Arylpyridines

by
Ricardo Riveiros
,
Rubén Tato
,
José Pérez Sestelo
* and
Luis A. Sarandeses
*
Centro de Investigaciones Científicas Avanzadas (CICA) and Departamento de Química, Universidade da Coruña, E-15071 A Coruña, Spain
*
Authors to whom correspondence should be addressed.
Molecules 2018, 23(7), 1582; https://doi.org/10.3390/molecules23071582
Submission received: 24 May 2018 / Revised: 13 June 2018 / Accepted: 26 June 2018 / Published: 29 June 2018
(This article belongs to the Special Issue Indium in Organic Synthesis)
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Versions Notes

Abstract

:
The activation of C–H bonds through catalytic reactions using transition metals is an important challenge in organic chemistry in which the intermediates are related to those produced in the classical cross-coupling reactions. As part of our research program devoted to the development of metal-catalyzed reactions using indium organometallics, a protocol for the C–H activation and C–C coupling of 2-arylpyridines with triorganoindium reagents under Rh(I) catalysis is reported. Under the optimized conditions, we found that Me3In and Ar3In reagents reacted with 2-arylpyridines and related compounds in the presence of Rh(PPh3)3Cl, in PhCl/THF (9:1), at 120 °C for 48 h, to afford the ortho-coupling products in moderate to good yields. The nitrogen atom in the pyridine ring acts as a directing group to assist the functionalization at the ortho position of the aryl group forming a new C–C bond at this position.

Graphical Abstract

1. Introduction

Since our discovery [1,2], the palladium catalyzed cross-coupling reaction of indium(III) organometallics has been established as a useful tool in organic synthesis [3,4]. In this reaction, triorganoindium reagents (R3In) can efficiently couple with a variety of organic electrophiles under palladium catalysis with high atom economy [5,6,7,8]. The process can be extended to other organoindium reagents [9,10,11,12,13] and transition metals in catalysis [14,15,16,17].
The formation of C–C bonds by C–H activation and cross-coupling with organometallics and related nucleophiles under transition metal catalysis constitutes a methodology of great interest due to the atom economy of the process and the challenge that represent the selective functionalization of one C–H bond [18,19]. Usually, a heteroatom acts as directing group for the C–H activation through coordination with the metal center to form a metallacycle that reacts with the organometallic to afford the coupling product (Scheme 1) [20,21]. In this field, Oi et al. reported the Rh(I)-catalyzed ortho-arylation of 2-phenylpyridines with organotin compounds [22], a catalytic system also used in related reactions using boronic acids [23]. In 2003, Murai et al. reported the Ru(II)-catalyzed ortho-arylation of aryl ketones with boronates [24]. After these pioneering contributions, some coupling reactions of organometallic species with C–H bonds under different transition metal catalysis (Pd, Rh, Ru, Fe, Ir) have been reported [25,26,27,28,29,30]. Among them, the C–H activation of 2-phenylpyridines with organometallic reagents and related nucleophiles constitutes an interesting topic, developed under palladium [31,32] and iron catalysis [33]. Despite the novelty of this methodology, and to the best of our knowledge, organoindium compounds have not been applied as carbon nucleophiles in transition metal catalyzed C–H functionalization. Herein, we report the first examples of C–H activation/cross-coupling reaction of R3In with 2-arylpyridines and related compounds under Rh catalysis.

2. Results and Discussion

Our research started by testing the reaction of triorganoindium reagents with 2-(p-tolyl)pyridine (1) under Rh(I) catalysis as a model. In this reaction, the nitrogen atom should serve as a directing group to activate a C–H bond forming a metallacycle, which, by a transmetallation and reductive elimination process, should afford the C–H activation/C–C cross-coupling product. At the outset, we found that the reaction of Me3In (100 mol %) with 1 in the presence of Rh(PPh3)3Cl (10 mol %) at 120 °C in THF gave methylated compound 2a in a low 16% yield after 48 h and most of the starting 2-(p-tolyl)pyridine recovered (Table 1, entry 1). Analogously, the reaction using Ph3In (100 mol %) gave 2b in 17% yield along with important amounts of 1,1′-biphenyl, formed by reductive dimerization of the organoindium in the reaction media (entry 2). Using other Rh(I) complexes such as Rh(cod)(acac), Rh(nbd)(acac) or [Rh(cod)Cl]2 combined with phosphines did not improve the yields (entries 3–6). The influence of the solvent was also studied and, considering that R3In are prepared as THF solutions, various solvent mixtures were used. Using toluene/THF (9:1) the reaction with Ph3In (100 mol %) and Rh(PPh3)3Cl (10 mol %) at 120 °C for 48 h gave 2b in a similar 18% yield (entry 7). Considering that polar non-protic chlorinated solvents have been successfully used in Rh(I)-catalyzed C–H activation reactions [22,34,35] 1,1,2,2-tetrachloroethane/THF (9:1) was tested as solvent, obtaining a 27% yield of 2b and a 4% of the o,o′-disubstituted product 2bb (entry 8). Considering that some of the starting 2-(p-tolyl)pyridine is recovered and part of the Ph3In is consumed with the formation of 1,1′-biphenyl, we decided to carry out the reaction using 150 mol % of Ph3In. Under these conditions, the yield of 2b increased up to 42% (along with a 16% of 2bb; entry 9). Analogously, the reaction using 150 mol % of Me3In also gave a satisfactory 60% yield of 2a (entry 10). Finally, we found that using chlorobenzene as cosolvent the reaction results in a good 80% yield of 2a using Me3In, and in 47% yield of 2b in the reaction with Ph3In (entries 11 and 12). Recently, Li et al. reported the arylation of arylpyridines under rhodium catalysis using chlorobenzene as solvent [35]. Interestingly, we observed that the use of chlorobenzene diminishes the formation of the o,o′-disubstituted product and that the conversion of the starting material is not complete under the reaction conditions.
With the optimized conditions in hand, we explored the versatility of the reaction using various 2-arylpyridines. The reaction of Me3In with 2-phenylpyridine (3) yielded the methylated compound 7a in a good 84% yield (and a 7% of the o,o′-dicoupled product 7aa, Table 2, entry 3). Alternatively, the reaction of Ph3In with 2-phenylpyridine (3) afforded 7b in 53% yield (6% of the disubstituted compound 7bb, entry 4).
The reaction was also tested with 2-(2-naphthyl)pyridine (4), a compound with two nonsymmetrical o-positions of the aryl group. Under the optimized conditions, the reaction of 4 with Me3In and Ph3In allowed the synthesis of 8a and 8b in 60% and 57% yields, respectively (entries 5 and 6) without isolation of the double coupling products. The selectivity for the first C–H activation in a substrate where the two ortho positions are different in terms of electron density and steric hindrance is remarkable.
Additionally, we also tested the reactivity of 2-phenylpyrimidine (5), a substrate possessing two nitrogen atoms. The reaction with Me3In under the optimized conditions, afforded 9a in 62% yield as the only product (entry 7). Using Ph3In, the monoarylated compound 9b was obtained in 57% yield, accompanied by the formation of a 7% yield of the disubstituted product 9bb (entry 8).
To improve the selectivity of the process, we used a rigid substrate such as benzo[h]quinoline (6) as starting material. In this case, the reaction of 6 with Me3In afforded 10a as the only reaction product in an excellent 93% yield (entry 9). Furthermore, the reaction of 6 with Ph3In afforded compound 10b in a 72% yield (entry 10). In these set of experiments, we demonstrated the efficiency of organoindium reagents in the transfer of methyl and phenyl groups in C–H coupling reactions with 2-arylpyridines.
At this point we also decided to test the versatility of the process using other triorganoindium reagents under the same reaction condition and using 1,1,2,2-tetrachloroethane as solvent. The reaction of trivinylindium with 6 afforded 10c in a modest 25% yield (entry 11). Alternatively, the reaction of 6 with other triarylindium species such as tris[4-(trifluoromethyl)phenyl]indium, tris(4-fluorophenyl)indium and tris(3-fluorophenyl)indium, under the usual conditions, led to the compounds 10d–f in moderated yields (20–45%; entries 12–14). Although the isolated yields of these last reactions might not be optimal, overall, these results represent the first examples of application of triorganoindium reagents in the Rh-catalyzed C–H activation and C–C cross-coupling with 2-arylpyridines and analogs and constitute a new entry in the reactivity of these compounds.
Although the mechanism of these reactions was not studied, based on previous reports [22,23,34], we believe the reaction proceeds via C–H activation of the ortho position of the 2-arylpyridine by an organorhodium(I) intermediate, which is generated by transmetallation of Rh(I)Cl species with the triorganoindium reagent. The resulting organoaryl(hydrido)rhodium species then undergoes reductive elimination to give the coupling product and a Rh(I)H species. Finally, the chlorinated solvent could participate in the regeneration of the active catalytic Rh(I) species by hydrogen/chloride exchange or HCl elimination. As for the proposal of Oi et al. [22], trichloroethylene was detected by 1H NMR of the reaction crude when 1,1,2,2-tetrachloroethane was used as solvent.

3. Materials and Methods

3.1. Materials and Reagents

All reactions were carried out in flamed dried glassware, under argon atmosphere, using standard gastight syringes, cannulas, and septa. Reaction temperatures refer to external bath temperatures. Anhydrous THF was obtained by distillation from the sodium ketyl of benzophenone. Chlorobenzene and 1,1,2,2-tetrachloroethane were dried and stored over microwave-activated 4 Å molecular sieves. All other commercially available reagents were used as received. Organolithium reagents (phenyllithium and methyllithium) were titrated prior to use. Organic extracts were dried over anhydrous MgSO4, filtered, and concentrated by using a rotary evaporator at aspirator pressure. Reactions were monitored by TLC using pre-coated silica gel plates (Alugram Xtra SIL G/UV254, 0.20 mm thick), UV light as the visualizing agent and ethanolic phosphomolybdic acid as the developing agent. Flash column chromatography was performed on silica gel (230–400 mesh). 1H and 13C NMR were recorded in CDCl3 at 300 MHz for 1H and 75 MHz for 13C, at 300 K, and calibrated to the solvent peak. DEPT data were used to assign carbon types (see Supplementary Materials). Mass spectra were obtained with EI ionization at 70 eV. IR spectra were recorded on a FT-IR spectrometer with an ATR (Attenuated Total Reflectance) accessory.

3.2. Preparation of Triorganoindium Reagents

Triorganoindium compounds were prepared according to previously published methods [36] by treatment of the corresponding organolithium reagent (3 equiv, ~0.5 M in THF) with a solution of InCl3 (1 equiv, 0.45 M in THF) at −78 °C and warming to room temperature. Organolithium reagents derived from 1-bromo-4-(trifluoromethyl)benzene, 1-bromo-4-fluorobenzene, 1-bromo-3-fluorobenzene and vinyl bromide were prepared by metal-halogen exchange reaction with t-BuLi (2 equiv) at −78 °C.

3.3. Preparation of Compounds 4 and 5

2-(2-Naphthyl)pyridine (4) [37]. To a solution of 2-bromopyridine (0.96 mL, 10.0 mmol) and Pd(dppf)Cl2 (408 mg, 0.5 mmol) in THF (50 mL), tri(2-naphthyl)indium (10.0 mmol, ~0.3 M in THF) was added. The mixture was stirred at 80 °C during 20 h, and the reaction was quenched by addition of drops of MeOH. The solvent was evaporated and EtOAc (25 mL) was added. The organic phase was washed with HCl (5%, 15 mL), satd. NH4Cl (15 mL) and brine (15 mL), dried, filtered, and concentrated. The crude was purified by flash chromatography (10% EtOAc/hexane), affording, after concentration and drying, 9 (1.05 g, 5.12 mmol, 51%) as a yellow solid. M.p. 69–70 °C (lit. [37], 77–78 °C); 1H NMR (CDCl3, 300 MHz) δ 7.27 (ddd, J = 7.2, 4.9, 1.0 Hz, 1 H), 7.50–7.55 (m, 2 H), 7.80 (td, J = 7.7, 1.8 Hz, 1 H), 7.87–7.97 (m, 4 H), 8.16 (dd, J = 8.6, 1.8 Hz, 1 H), 8.50 (d, J = 1.5 Hz, 1 H), 8.77 (ddd, J = 4.9, 1.5, 1.0 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz) δ 120.8 (CH), 122.1 (CH), 124.5 (CH), 126.3 (CH), 126.3 (CH), 126.5 (CH), 127.6 (CH), 128.4 (CH), 128.7 (CH), 133.5 (C), 133.6 (C), 136.6 (C), 136.8 (CH), 149.7 (CH), 157.3 (C) ppm; IR (ATR) 3053, 3010, 2919, 2849 cm−1; MS (EI) m/z (%) 205 (M+, 100), 204 ([M − H]+, 75); HRMS (EI) m/z calcd for C15H11N 205.0886, found 205.0881.
2-Phenylpyrimidine (5) [38]. To a solution of 2-chloropyrimidine (1.21 g, 10.0 mmol) and Pd(dppf)Cl2 (408 mg, 0.5 mmol) in THF (50 mL), triphenylindium (4.0 mmol, ~0.3 M en THF) was added. The mixture was stirred at 80 °C for 4 h and the reaction quenched by addition of drops of MeOH. The solvent was evaporated and EtOAc (25 mL) was added. The organic phase was washed with HCl (5%, 15 mL), satd. NH4Cl (15 mL) and brine (15 mL), dried, filtered, and concentrated. The crude was purified by flash chromatography (20% EtOAc/hexane) affording, after concentration and drying, 12 (1.42 g, 9.09 mmol, 91%) as a white solid. M.p. 36–38 °C (lit. [38], 36–38 °C). 1H NMR (CDCl3, 300 MHz) δ 6.95 (t, J = 4.9 Hz, 1 H), 7.42–7.49 (m, 3 H), 8.47–8.50 (m, 2 H), 8.66 (d, J = 4.9 Hz, 2 H) ppm; 13C NMR (CDCl3, 75 MHz) δ 119.0 (CH), 128.2 (2 × CH), 128.6 (2 × CH), 130.8 (CH), 137.5 (C), 157.1 (2 × CH), 164.5 (C) ppm; IR (ATR) 3087, 3066, 3039 cm−1; MS (EI) m/z (%) 156 (M+, 92), 103 (100); HRMS (EI) m/z calcd for C10H8N2 156.0682, found 156.0683.

3.4. General Procedure C–H Activation/C–C Cross-Coupling with Indium(III) Organometallics under Rhodium Catalysis

In a Schlenk tube, a solution of R3In (0.375 mmol, ~0.3 M en THF) and the arylpyridine (0.25 mmol) were successively added to a solution of Rh(PPh3)3Cl (24 mg, 0.025 mmol) in chlorobenzene (20 mL). The mixture was stirred at 120 °C during 48 h, and the reaction quenched by addition of drops of MeOH. The solvent was evaporated and CHCl3 (25 mL) was added. The organic phase was washed with aq. NH3 (5%, 15 mL), dried, filtered, and concentrated. The crude was purified by flash chromatography (Et2O/hexane) affording, after concentration and drying, the cross-coupling products.
2-(2,4-Dimethylphenyl)pyridine (2a) [39]. Colorless oil (37 mg, 0.200 mmol, 80%). 1H NMR (CDCl3, 300 MHz) δ 2.35 (s, 3 H), 2.38 (s, 3 H), 7.10 (d, J = 7.7 Hz, 2 H), 7.23 (ddd, J = 7.5, 4.9, 1.0 Hz, 1 H), 7.31 (d, J = 7.5 Hz, 1 H), 7.39 (dt, J = 7.9, 1.0 Hz, 1 H), 7.73 (td, J = 7.7, 1.8 Hz, 1 H), 8.69 (ddd, J = 4.9, 1.8, 1.0 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz) δ 20.2 (CH3), 21.1 (CH3), 121.3 (CH), 124.0 (CH), 126.5 (CH), 129.6 (CH), 131.4 (CH), 135.5 (C), 135.9 (CH), 137.6 (C), 137.9 (C), 149.1 (CH), 160.1 (C) ppm; IR (ATR) 2954, 2922, 2853, 2360 cm−1; MS (EI) m/z (%) 183 (M+, 44), 182 ([M − H]+, 100); HRMS (EI) m/z calcd for C13H13N 183.1043, found 183.1027.
2-(2,4,6-trimethylphenyl)pyridine (2aa) [40]. Colorless oil (6 mg, 0.030 mmol, 12%) 1H NMR (CDCl3, 300 MHz) δ 2.03 (s, 6 H), 2.33 (s, 3 H), 6.94 (s, 2 H), 7.24–7.30 (m, 2 H), 7.18 (td, J = 7.7, 1.6 Hz, 1 H), 8.72–8.74 (m, 1 H) ppm; 13C NMR (CDCl3, 75 MHz) δ 20.0 (2 × CH3), 21.0 (CH3), 121.6 (CH), 124.8 (CH), 128.3 (2 × CH), 135.2 (C), 135.6 (2 × C), 136.5 (CH), 137.5 (C), 149.2 (CH), 159.7 (C) ppm; IR (ATR) 2952, 2921, 2855, 2358 cm−1; MS (EI) m/z (%) 197 (M+, 34), 196 ([M − H]+, 100); HRMS (EI) m/z calcd for C14H15N 197.1199, found 197.1181.
2-(5-Methyl[1,1′-biphenyl]-2-yl)pyridine (2b) [41]. White solid (29 mg, 0.118 mmol, 47%). 1H NMR (CDCl3, 300 MHz) δ 2.46 (s, 3 H), 6.86 (dt, J = 7.9, 1.0 Hz, 1 H), 7.08 (ddd, J = 7.5, 4.9, 1.0 Hz, 1 H), 7.14–7.19 (m, 2 H), 7.21–7.31 (m, 5 H), 7.36 (td, J = 7.7, 1.8 Hz, 1 H), 7.63 (d, J = 7.7 Hz, 1 H), 8.63 (ddd, J = 4.9, 1.8, 1.0 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz) δ 21.2 (CH3), 121.0 (CH), 125.3 (CH), 126.6 (CH), 128.0 (2 × CH), 128.3 (CH), 129.6 (2 × CH), 130.4 (CH), 131.2 (CH), 135.0 (CH), 136.7 (C), 138.3 (C), 140.4 (C), 141.5 (C), 149.3 (CH), 159.2 (C) ppm; IR (ATR) 3025, 2921, 2852 cm−1; MS (EI) m/z (%) 245 (M+, 32), 244 ([M − H]+, 100); HRMS (ESI) m/z calcd for C18H16N ([M + H]+) 246.1277, found 246.1275.
2-(5′-Methyl[1,1′:3′,1′’-terphenyl]-2′-yl)pyridine (2bb) [42]. White solid. (5 mg, 0.015 mmol, 6%) 1H NMR (CDCl3, 300 MHz) δ 2.49 (s, 3 H), 6.85–6.92 (m, 2 H), 7.09–7.18 (m, 10 H), 7.26–7.32 (m, 3 H), 8.31 (ddd, J = 4.9, 1.6, 1.0 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz) δ 21.2 (CH3), 120.6 (CH), 126.1 (2 × CH), 126.8 (CH), 127.5 (4 × CH), 129.6 (4 × CH), 130.1 (2 × CH), 134.7 (CH), 135.8 (C), 137.7 (C), 141.7 (2 × C), 141.7 (2 × C), 148.4 (CH), 159.0 (C) ppm; IR (ATR) 3054, 3026, 2955, 2922, 2852 cm−1; MS (EI) m/z (%) 321 (M+, 52), 320 ([M − H]+, 100); HRMS (ESI) m/z calcd for C24H20N ([M + H]+) 322.1590, found 322.1589.
2-(2-Methylphenyl)pyridine (7a) [43]. Colorless oil (36 mg, 0.210 mmol, 84%). 1H NMR (CDCl3, 300 MHz) δ 2.38 (s, 3 H), 7.23–7.32 (m, 4 H), 7.39–7.43 (m, 2 H), 7.75 (td, J = 7.7, 1.9 Hz, 1 H), 8.71 (ddd, J = 4.9, 1.9, 1.0 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz) δ 20.2 (CH3), 121.5 (CH), 124.0 (CH), 125.8 (CH), 128.2 (CH), 129.6 (CH), 130.7 (CH), 135.7 (C), 136.0 (CH), 140.4 (C), 149.2 (CH), 160.0 (C) ppm; IR (ATR) 3059, 2924, 2359 cm−1; MS (EI) m/z (%) 169 (M+, 34), 168 ([M − H]++, 100); HRMS (EI) m/z calcd for C12H10N ([M − H]+) 168.0808, found 168.0814.
2-(2,6-dimethylphenyl)pyridine (7aa) [39]. Colorless oil (3 mg, 0.016 mmol, 7%) 1H NMR (CDCl3, 300 MHz) δ 2.05 (s, 6 H), 7.10–7.12 (m, 2 H), 7.18–7.29 (m, 3 H), 7.77 (td, J = 7.7, 1.9 Hz, 1 H), 8.73 (ddd, J = 4.9, 1.9, 1.0 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz) δ 20.1 (2 × CH3), 121.6 (CH), 124.4 (CH), 127.5 (2 × CH), 127.8 (CH), 135.7 (2 × C), 136.2 (CH), 140.4 (C), 149.7 (CH), 159.9 (C) ppm; IR (ATR) 2924, 2854, 2360, 2214 cm−1; MS (EI) m/z (%) 183 (M+, 35), 182 ([M − H]+, 100); HRMS (EI) m/z calcd for C13H12N ([M − H]+) 182.0964, found 182.0963.
2-[1,1′-Biphenyl]-2-yl-pyridine (7b) [44]. White solid (31 mg, 0.132 mmol, 53%). M.p. 86–87 °C (lit. [44], 86.5–87.5 °C); 1H NMR (CDCl3, 300 MHz) δ 6.89 (dt, J = 7.9, 1.0 Hz, 1 H), 7.10 (ddd, J = 7.5, 4.9, 1.0 Hz, 1 H), 7.15–7.19 (m, 2 H), 7.22–7.25 (m, 3 H), 7.39 (td, J = 7.7, 1.8 Hz, 1 H), 7.41–7.51 (m, 3 H), 7.69–7.74 (m, 1 H), 8.64 (ddd, J = 4.9, 1.8, 1.0 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz) δ 121.3 (CH), 125.3 (CH), 126.6 (CH), 127.6 (CH), 128.0 (2 × CH), 128.5 (CH), 129.7 (2 × CH), 130.4 (2 × CH), 135.1 (CH), 139.4 (C), 140.6 (C), 141.3 (C), 149.4 (CH), 159.2 (C) ppm; IR (ATR) 3052, 3018, 2919, 2850 cm−1; MS (EI) m/z (%) 231 (M+, 26), 230 ([M − H]+, 100); HRMS (ESI) m/z calcd for C17H14N ([M + H]+) 232.1120, found 232.1123.
2-[1,1′:3′,1′’-terphenyl]-2′-yl-pyridine (7bb) [44]. White solid (4 mg, 0.013 mmol, 6%) M.p. 123–124 °C (lit. [44], 118–119.5 °C); 1H NMR (CDCl3, 300 MHz) δ 6.88–6.94 (m, 2 H), 7.10–7.18 (m, 10 H), 7.30 (td, J = 7.7, 1.8 Hz, 1 H), 7.45–7.48 (m, 2 H), 7.52–7.57 (m, 1 H), 8.33 (ddd, J = 4.8, 1.8, 1.0 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz) δ 120.8 (CH), 126.2 (2 × CH), 126.7 (CH), 127.6 (4 × CH), 128.1 (CH), 129.4 (2 × CH), 129.6 (4 × CH), 134.8 (CH), 138.5 (C), 141.6 (2 × C), 141.8 (2 × C), 148.5 (CH), 158.9 (C); IR (ATR) 3056, 2923 cm−1; MS (EI) m/z (%) 307 (M+, 51), 306 ([M − H]+, 100); HRMS (ESI) m/z calcd for C23H18N ([M + H]+) 308.1433, found 308.1429.
2-(3-Methyl-2-naphthyl)pyridine (8a) [39]. White solid (33 mg, 0.150 mmol, 60%). M.p. 79–80 °C; 1H NMR (CDCl3, 300 MHz) δ 2.53 (s, 3 H), 7.29 (ddd, J = 8.2, 5.2, 1.5 Hz, 1 H), 7.42–7.53 (m, 3 H), 7.75–7.87 (m, 4 H), 7.89 (s, 1 H), 8.76 (ddd, J = 4.9, 1.8, 1.0 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz) δ 20.8 (CH3), 121.7 (CH), 124.2 (CH), 125.4 (CH), 126.3 (CH), 126.9 (CH), 127.9 (CH), 128.7 (CH), 128.8 (CH), 131.9 (C), 133.4 (C), 133.8 (C), 136.2 (CH), 139.4 (C), 149.2 (CH), 160.0 (C) ppm; IR (ATR) 3052, 3007, 2958, 2920, 2849 cm−1; MS (EI) m/z (%) 219 (M+, 57), 218 ([M − H]+, 100); HRMS (EI) m/z calcd for C16H13N 219.1043, found 219.1035.
2-(3-Phenyl-2-naphthyl)pyridine (8b) [44]. Brown solid (40 mg, 0.142 mmol, 57%). M.p. 107–108 °C (lit. [44], 103.5–106 °C); 1H NMR (CDCl3, 300 MHz) δ 6.98 (dt, J = 7.9, 1.0 Hz, 1 H), 7.14 (ddd, J = 7.5, 4.9, 1.0 Hz, 1 H), 7.28 (s, 5 H), 7.43 (td, J = 7.7, 1.8 Hz, 1 H), 7.52–7.55 (m, 2 H), 7.89–7.97 (m, 3 H), 8.22 (s, 1 H), 8.68 (ddd, J = 4.9, 1.8, 1.0 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz) δ 121.4 (CH), 125.5 (CH), 126.3 (CH), 126.7 (CH), 126.7 (CH), 127.7 (CH), 128.0 (2 × CH), 128.2 (CH), 129.5 (CH), 129.8 (2 × CH), 130.1 (CH), 132.6 (C), 133.2 (C), 135.1 (CH), 137.8 (C), 138.5 (C), 141.3 (C), 149.4 (CH), 159.1 (C) ppm; IR (ATR) 3054, 2923, 2853 cm−1; MS (EI) m/z (%) 281 (M+, 47), 280 ([M − H]+, 100); HRMS (EI) m/z calcd for C21H14N ([M − H]+) 280.1121, found 280.1126.
2-(2-Methylphenyl)pyrimidine (9a) [45]. Pale yellow oil (26 mg, 0.155 mmol, 62%). 1H NMR (CDCl3, 300 MHz) δ 2.56 (s, 3 H), 7.22 (t, J = 4.9 Hz, 1 H), 7.27–7.36 (m, 3 H), 7.80–7.83 (m, 1 H), 8.85 (d, J = 4.9 Hz, 2 H) ppm; 13C NMR (CDCl3, 75 MHz) δ 20.9 (CH3), 118.4 (CH), 125.8 (CH), 129.4 (CH), 130.3 (CH), 131.2 (CH), 137.1 (C), 138.1 (C), 156.8 (2 × CH), 167.7 (C) ppm; IR (ATR) 3034, 2924, 2853 cm−1; MS (EI) m/z (%) 170 (M+, 73), 169 ([M − H]+, 100); HRMS (EI) m/z calcd for C11H10N2 170.0838, found 170.0830.
2-[1,1′-Biphenyl]-2-yl-pyrimidine (9b) [46]. White solid (33 mg, 0.142 mmol, 57%). M.p. 100–102 °C (lit. [46], 102–103 °C); 1H NMR (CDCl3, 300 MHz) δ 7.10 (t, J = 4.9 Hz, 1 H), 7.14–7.18 (m, 2 H), 7.21–7.27 (m, 3 H), 7.46–7.56 (m, 3 H), 7.80–7.83 (m, 1 H), 8.64 (d, J = 4.9 Hz, 2 H) ppm; 13C NMR (CDCl3, 75 MHz) δ 118.4 (CH), 126.4 (CH), 127.3 (CH), 127.9 (2 × CH), 129.1 (2 × CH), 129.3 (CH), 130.4 (CH), 130.7 (CH), 138.2 (C), 141.4 (C), 141.6 (C), 156.7 (2 × CH), 168.1 (C) ppm; IR (ATR) 3057, 3024, 2922, 2852, 2326 cm−1; MS (EI) m/z (%) 232 (M+, 25), 231 ([M − H]+, 100); HRMS (EI) m/z calcd for C16H11N2 ([M − H]+) 231.0917, found 231.0915.
2-[1,1′:3′,1′’-terphenyl]-2′-yl-pyrimidine (9bb) [46]. White solid (5 mg, 0.016 mmol, 7%) M.p. 145–146 °C (lit. [46], 146–148 °C); 1H NMR (CDCl3, 300 MHz) δ 6.92 (t, J = 4.9 Hz, 1 H), 7.12–7.20 (m, 10 H), 7.48 (dd, J = 7.5, 1.0 Hz, 2 H), 7.57 (dd, J = 8.7, 6.4 Hz, 1 H), 8.46 (d, J = 4.9 Hz, 2 H) ppm; 13C NMR (CDCl3, 75 MHz) δ 118.0 (CH), 126.4 (2 × CH), 127.8 (4 × CH), 128.6 (CH), 129.1 (4 × CH), 129.2 (2 × CH), 137.6 (C), 141.3 (2 × C), 141.4 (2 × C), 155.9 (2 × CH), 168.1 (C) ppm; IR (ATR) 3058, 2918, 2850, 2324 cm−1; MS (EI) m/z (%) 308 (M+, 76), 307 ([M − H]+, 100); HRMS (EI) m/z calcd for C22H15N2 ([M − H]+) 307.1230, found 307.1231.
10-Methylbenzo[h]quinoline (10a) [38]. White solid (45 mg, 0.232 mmol, 93%). M.p. 70–71 °C; 1H NMR (CDCl3, 300 MHz) δ 3.40 (s, 3 H), 7.49 (dd, J = 8.0, 4.3 Hz, 1 H), 7.57–7.60 (m, 2 H), 7.66 (d, J = 8.8 Hz, 1 H), 7.80–7.83 (m, 2 H), 8.16 (dd, J = 8.0, 1.9 Hz, 1 H), 9.06 (dd, J = 4.3, 1.9 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz) δ 27.2 (CH3), 120.5 (CH), 125.4 (CH), 126.7 (CH), 127.2 (CH), 127.4 (C), 128.8 (CH), 129.9 (C), 131.1 (CH), 135.1 (C), 135.2 (CH), 138.7 (C), 147.1 (CH), 149.0 (C) ppm; IR (ATR) 3046, 2960, 2922, 2851, 2740 cm−1; MS (EI) m/z (%) 193 (M+, 100), 192 ([M − H]+, 66); HRMS (ESI) m/z calcd for C14H12N ([M + H]+) 194.0964, found 194.0961.
10-Phenylbenzo[h]quinoline (10b) [44]. Yellow oil (46 mg, 0.180 mmol, 72%). 1H NMR (CDCl3, 300 MHz) δ 7.33 (dd, J = 8.0, 4.3 Hz, 1 H), 7.36–7.42 (m, 5 H), 7.56 (dd, J = 7.3, 1.4 Hz, 1 H), 7.67–7.72 (m, 2 H), 7.87 (d, J = 8.8 Hz, 1 H), 7.94 (dd, J = 8.0, 1.4 Hz, 1 H), 8.09 (dd, J = 8.0, 1.9 Hz, 1 H), 8.44 (dd, J = 4.3, 1.9 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz) δ 121.0 (CH), 125.6 (CH), 125.9 (CH), 127.0 (CH), 127.2 (C), 127.3 (2 × CH), 127.9 (CH), 128.2 (CH), 128.7 (2 × CH), 129.0 (C), 131.4 (CH), 134.9 (C), 135.1 (CH), 141.7 (C), 146.4 (C), 146.8 (C), 146.8 (CH) ppm; IR (ATR) 3049, 3028, 2923 cm−1; MS (EI) m/z (%) 255 (M+, 27), 254 ([M − H]+, 100); HRMS (ESI) m/z calcd for C19H14N ([M + H]+) 256.1120, found 256.1113.
10-Ethenylbenzo[h]quinoline (10c) [47]. Yellow oil (13 mg, 0.0625 mmol, 25%). 1H NMR (CDCl3, 300 MHz) δ 5.41 (dd, J = 10.8, 1.9 Hz, 1 H), 5.63 (dd, J = 17.3, 1.9 Hz, 1 H), 7.51 (dd, J = 8.0, 4.3 Hz, 1 H), 7.65–7.70 (m, 2 H), 7.80–7.84 (m, 2 H), 7.89 (dd, J = 8.0, 1.3 Hz, 1 H), 8.18 (dd, J = 8.0, 1.9 Hz, 1 H), 8.61 (dd, J = 17.3, 10.8 Hz, 1 H), 9.06 (dd, J = 4.3, 1.9 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz) δ 112.5 (CH2), 120.9 (CH), 125.6 (CH), 127.6 (CH), 128.3 (CH), 128.54 (CH), 128.55 (CH), 134.7 (2 × C), 135.6 (CH), 139.2 (2 × C), 142.4 (CH), 147.6 (CH), 148.1 (C) ppm; IR (ATR) 3047, 2923, 2852, 2359 cm−1; MS (EI) m/z (%) 205 (M+, 27), 204 ([M − H]+, 100); HRMS (EI) m/z calcd for C15H10N ([M − H]+) 204.0808, found 204.0807.
10-[4-(Trifluoromethyl)phenyl]benzo[h]quinoline (10d) [48]. Yellow oil (16 mg, 0.0495 mmol, 20%). 1H NMR (CDCl3, 300 MHz) δ 7.35 (dd, J = 8.0, 4.3 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 2 H), 7.51 (dd, J = 7.3, 1.1 Hz, 1 H), 7.66 (d, J = 8.0 Hz, 2 H), 7.71 (t, J = 7.3 Hz, 1 H), 7.72 (d, J = 8.8 Hz, 1 H), 7.89 (d, J = 8.8 Hz, 1 H), 7.98 (dd, J = 8.0, 1.4 Hz, 1 H), 8.11 (dd, J = 8.0, 1.8 Hz, 1 H), 8.40 (dd, J = 4.3, 1.8 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz) δ 121.3 (CH), 124.3 (q, 3JCF = 3.8 Hz, 2 × CH), 124.7 (q, 1JCF = 271.7 Hz, CF3), 126.1 (CH), 127.1 (CH), 127.3 (C), 127.7 (q, 2JCF = 31.7 Hz, C), 128.2 (CH), 128.5 (CH), 128.8 (C), 128.9 (2 × CH), 131.1 (CH), 134.9 (C), 135.3 (CH), 140.2 (C), 146.4 (C), 146.9 (CH), 150.2 (C) ppm; IR (ATR) 2928 cm−1; MS (EI) m/z (%) 323 (M+, 30), 322 ([M − H]+, 100); HRMS (ESI) m/z calcd for C20H13NF3 ([M + H]+) 324.0994, found 324.0993.
10-[4-(Fluorophenyl)benzo[h]quinoline (10e) [48]. Yellow oil (31 mg, 0.113 mmol, 45%). 1H NMR (CDCl3, 300 MHz) δ 7.07–7.13 (m, 2 H), 7.27–7.37 (m, 3 H), 7.53 (dd, J = 7.3, 1.4 Hz, 1 H), 7.69 (t, J = 7.6 Hz, 1 H), 7.71 (d, J = 9.1 Hz, 1 H), 7.87 (d, J = 8.8 Hz, 1 H), 7.94 (dd, J = 8.0, 1.4 Hz, 1 H), 8.10 (dd, J = 8.0, 1.9 Hz, 1 H), 8.46 (dd, J = 4.3, 1.9 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz) δ 114.1 (d, 2JCF = 21.3 Hz, 2 × CH), 121.1 (CH), 126.0 (CH), 127.0 (CH), 127.2 (C), 128.1 (CH), 128.3 (CH), 129.0 (C), 130.1 (d, 3JCF = 7.8 Hz, 2 × CH), 131.5 (CH), 135.0 (C), 135.3 (CH), 140.6 (C), 142.2 (d, 4JCF = 3.5 Hz, C), 146.7 (C), 146.8 (CH), 161.5 (d, 1JCF = 243.1 Hz, CF) ppm; IR (ATR) 3049, 2926, 2870 cm−1; MS (EI) m/z (%) 273 (M+, 28), 272 ([M − H]+, 100); HRMS (ESI) m/z calcd for C19H13NF ([M + H]+) 274.1026, found 274.1022.
10-[3-(Fluorophenyl)benzo[h]quinoline (10f). Yellow oil (21 mg, 0.075 mmol, 30%). 1H NMR (CDCl3, 300 MHz) δ 7.03–7.08 (m, 2 H), 7.12–7.15 (m, 1 H), 7.32–7.38 (m, 2 H), 7.54 (dd, J = 7.3, 1.4 Hz, 1 H), 7.70 (t, J = 7.6 Hz, 1 H), 7.72 (d, J = 8.8 Hz, 1 H), 7.87 (d, J = 8.8 Hz, 1 H), 7.96 (dd, J = 8.0, 1.4 Hz, 1 H), 8.11 (dd, J = 8.0, 1.9 Hz, 1 H), 8.46 (dd, J = 4.3, 1.9 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz) δ 112.4 (d, 2JCF = 21.1 Hz, CH), 115.8 (d, 2JCF = 21.5 Hz, CH), 121.2 (CH), 124.4 (d, 4JCF = 2.7 Hz, CH), 126.1 (CH), 127.0 (CH), 127.2 (C), 128.2 (CH), 128.3 (CH), 128.7 (d, 3JCF = 8.5 Hz, CH), 128.9 (C), 131.1 (CH), 134.9 (C), 135.2 (CH), 140.3 (d, 4JCF = 2.0 Hz, C), 146.5 (C), 147.0 (CH), 148.6 (d, 3JCF = 8.3 Hz, C), 162.4 (d, 1JCF = 243.3 Hz, CF) ppm; IR (ATR) 3048, 2955, 2924, 2854 cm−1; MS (EI) m/z (%) 273 (M+, 30), 272 ([M − H]+, 100); HRMS (ESI) m/z calcd for C19H13NF ([M + H]+) 274.1026, found 274.1023.

4. Conclusions

In summary, we report a novel protocol for the C–H activation and C–C coupling of 2-arylpyridines with triorganoindium reagents under rhodium catalysis. Reactions proceeded regioselectively to the ortho position of the aryl group with methyl- and phenylindium reagents in moderate to good yields. The use of chlorobenzene as solvent is useful to minimize the o,o′-disubstituted products. This contribution represents a new entry about the reactivity of organoindium reagents and could help to develop further studies on C–H activation reactions. Additionally, the reactions reported represent a new example for the transmetallation of organic groups from indium to rhodium.

Supplementary Materials

The following are available online at https://www.mdpi.com/1420-3049/23/7/1582/s1: Copies of 1H NMR and 13C NMR spectra of the compounds 2, 4, 5 and 7–10.

Author Contributions

L.A.S., J.P.S. and R.R. conceived and designed the experiments; R.T. performed the experiments and analyzed the data; L.A.S., J.P.S. and R.R. wrote the paper.

Funding

We gratefully acknowledge the Spanish Ministerio de Economía y Competitividad (CTQ2015-68369-P), Xunta de Galicia (GRC2014/042) and EDRF funds for financial support.

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds 2a, 2b, 7a, 7b, 8a, 8b, 9a, 9b, 10a, 10b are available from the authors.
Molecules 23 01582 sch001 550
Scheme 1. C–H activation/C–C cross coupling reactions.
Scheme 1. C–H activation/C–C cross coupling reactions.
Molecules 23 01582 sch001
Table
Table 1. Reaction of indium organometallics with 2-(p-tolyl)pyridine under rhodium catalysis 1.
Table 1. Reaction of indium organometallics with 2-(p-tolyl)pyridine under rhodium catalysis 1.
Molecules 23 01582 i001
EntryR (mol % of R3In)CatalystSolventYield (%) 2
1Me (100)Rh(PPh3)3ClTHF16
2Ph (100)Rh(PPh3)3ClTHF17
3Me (100)Rh(cod)(acac)THF14
4Me (100)Rh(nbd)(acac)THF15
5 3Me (100)[Rh(cod)Cl]2, Ph3PTHF14
6 3Me (100)[Rh(cod)Cl]2, Cy3PTHF15
7Ph (100)Rh(PPh3)3ClToluene/THF (9:1)18
8Ph (100)Rh(PPh3)3ClCl2CHCHCl2/THF (9:1)27 (4)
9Ph (150)Rh(PPh3)3ClCl2CHCHCl2/THF (9:1)42 (16)
10Me (150)Rh(PPh3)3ClCl2CHCHCl2/THF (9:1)60 (34)
11Me (150)Rh(PPh3)3ClPhCl/THF (9:1)80 (12)
12Ph (150)Rh(PPh3)3ClPhCl/THF (9:1)47 (6)
1 Reactions performed in a Schlenk tube using 10 mol % of the rhodium complex at 120 °C for 48 h. 2 In parentheses, yield of the o,o′-dicoupling product (2aa, 2bb) obtained. 3 5 mol % of rhodium complex and 20 mol % of phosphine used.
Table
Table 2. Reaction of R3In with 2-arylpyridines under rhodium catalysis 1.
Table 2. Reaction of R3In with 2-arylpyridines under rhodium catalysis 1.
Molecules 23 01582 i002
Entry2-ArylpyridineRProductYield (%) 2
1 Molecules 23 01582 i003Me Molecules 23 01582 i00480 (12)
2 Ph Molecules 23 01582 i00547 (6)
3 Molecules 23 01582 i006Me Molecules 23 01582 i00784 (7)
4 Ph Molecules 23 01582 i00853 (6)
5 Molecules 23 01582 i009Me Molecules 23 01582 i01060
6 Ph Molecules 23 01582 i01157
7 Molecules 23 01582 i012Me Molecules 23 01582 i01362
8 Ph Molecules 23 01582 i01457 (7)
9 Molecules 23 01582 i015Me Molecules 23 01582 i01693
10 Ph Molecules 23 01582 i01772
11 CH2=CH Molecules 23 01582 i01825 3
12 4-CF3C6H4 Molecules 23 01582 i01920 3
13 4-FC6H4 Molecules 23 01582 i02045 3
14 3-FC6H4 Molecules 23 01582 i02130 3
1 Reactions performed in a Schlenk tube using 10 mol % of the rhodium complex at 120 °C for 48 h. 2 In parentheses, yield of the o,o′-dicoupling product obtained. 3 Cl2CHCHCl2/THF (9:1) was used as solvent.

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MDPI and ACS Style

Riveiros, R.; Tato, R.; Pérez Sestelo, J.; Sarandeses, L.A. Triorganoindium Reagents in Rh-Catalyzed C–H Activation/C–C Cross-Coupling Reactions of 2-Arylpyridines. Molecules 2018, 23, 1582. https://doi.org/10.3390/molecules23071582

AMA Style

Riveiros R, Tato R, Pérez Sestelo J, Sarandeses LA. Triorganoindium Reagents in Rh-Catalyzed C–H Activation/C–C Cross-Coupling Reactions of 2-Arylpyridines. Molecules. 2018; 23(7):1582. https://doi.org/10.3390/molecules23071582

Chicago/Turabian Style

Riveiros, Ricardo, Rubén Tato, José Pérez Sestelo, and Luis A. Sarandeses. 2018. "Triorganoindium Reagents in Rh-Catalyzed C–H Activation/C–C Cross-Coupling Reactions of 2-Arylpyridines" Molecules 23, no. 7: 1582. https://doi.org/10.3390/molecules23071582

APA Style

Riveiros, R., Tato, R., Pérez Sestelo, J., & Sarandeses, L. A. (2018). Triorganoindium Reagents in Rh-Catalyzed C–H Activation/C–C Cross-Coupling Reactions of 2-Arylpyridines. Molecules, 23(7), 1582. https://doi.org/10.3390/molecules23071582

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